Synthesis Of Small-molecule Libraries Research Articles

Diversity-oriented synthetic strategy for developing a chemical modulator of protein-protein interaction.

Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase–RagD protein–protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure-based DOS strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets.

ChemInform Abstract: Recent Advances in Multicomponent Reactions for Diversity‐Oriented Synthesis

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Bioactivity-Guided Navigation of Chemical Space

A central aim of biological research is to elucidate the many roles of proteins in complex, dynamic living systems; the selective perturbation of protein function is an important tool in achieving this goal. Because chemical perturbations offer opportunities often not accessible with genetic methods, the development of small-molecule modulators of protein function is at the heart of chemical biology research. In this endeavor, the identification of biologically relevant starting points within the vast chemical space available for the design of compound collections is a particularly relevant, yet difficult, task. In this Account, we present our research aimed at linking chemical and biological space to define suitable starting points that guide the synthesis of compound collections with biological relevance. Both protein folds and natural product (NP) scaffolds are highly conserved in nature. Whereas different amino acid sequences can make up ligand-binding sites in proteins with highly similar fold types, differently substituted NPs characterized by particular scaffold classes often display diverse biological activities. Therefore, we hypothesized that (i) ligand-binding sites with similar ligand-sensing cores embedded in their folds would bind NPs with similar scaffolds and (ii) selectivity is ensured by variation of both amino acid side chains and NP substituents. To investigate this notion in compound library design, we developed an approach termed biology-oriented synthesis (BIOS). BIOS employs chem- and bioinformatic methods for mapping biologically relevant chemical space and protein space to generate hypotheses for compound collection design and synthesis. BIOS also provides hypotheses for potential bioactivity of compound library members. On the one hand, protein structure similarity clustering (PSSC) is used to identify ligand binding sites with high subfold similarity, that is, high structural similarity in their ligand-sensing cores. On the other hand, structural classification by scaffold trees (for example, structural classification of natural products or SCONP), when combined with software tools like "Scaffold Hunter", enables the hierarchical structural classification of small-molecule collections in tree-like arrangements, their annotation with bioactivity data, and the intuitive navigation of chemical space. Brachiation (in a manner analogous to tree-swinging primates) within the scaffold trees serves to identify new starting points for the design and synthesis of small-molecule libraries, and PSSC may be used to select potential protein targets. The introduction of chemical diversity in compound collections designed according to the logic of BIOS is essential for the frequent identification of small molecules with diverse biological activities. The continuing development of synthetic methodology, both on solid phase and in solution, enables the generation of focused small-molecule collections with sufficient substituent, stereochemical, and scaffold diversity to yield comparatively high hit rates in biochemical and biological screens from relatively small libraries. BIOS has also allowed the identification of new ligand classes for several different proteins and chemical probes for the study of protein function in cells.

Recent advances in multicomponent reactions for diversity-oriented synthesis

Interest in multicomponent reactions (MCRs) has surged during the past two decades as interest in the efficient synthesis of small molecule libraries has gained prominence. MCRs fill an important niche in library synthesis by providing direct access to library compounds and by serving as starting points for Diversity-Oriented Synthesis (DOS). Recent advances in the area of MCR chemistry have included the discovery of new reactions, development of the first asymmetric catalysts, and the application of MCRs to natural products and other targets of biological interest. This review will highlight recent developments in MCRs as a rich source of molecular diversity.

Combinatorial approach toward synthesis of small molecule libraries as bacterial transglycosylase inhibitors

The development of iminocyclitol-based small molecule libraries against a bacterial TGase is described. An iminocyclitol was conjugated with a pyrophosphate mimic using either a 1,3-dipolar cycloaddition or reductive amination reaction, which was then condensed with a variety of lipophilic carboxylic acids in an amide bond coupling to generate a desired molecular library. With assistance of microtiter plate-based combinatorial chemistry and in situ screening, a potential inhibitor, the first potent iminocyclitol-based inhibitor against bacterial TGases was efficiently developed.

Diversity Oriented Synthesis of Small Molecule Libraries

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Combinatorial Synthesis of Small Molecule Libraries by Microwave Technology

Combinatorial Synthesis of Small Molecule Libraries by Microwave Technology

Optimization of solid supports for combinatorial chemical synthesis.

Until recently, resins were used primarily for peptide and oligonucleotide synthesis. Recent advances in combinatorial chemistry have fostered increased acceptance of resins as supports for the synthesis of small molecule libraries. The methodology for selecting a resin bead that is ideal for the solid phase synthesis of small molecules is described in this review. The process of manufacturing a typical resin, the UniSphere-200, is also explained. Furthermore, a new approach is proposed for the solid phase synthesis of analogs which are traditionally done in solution phase. This new procedure involves the use of building blocks attached to an activated resin. These building blocks are displaced by a functional group on the scaffold around which the analogs are built. Use of an excess of resin-linked building blocks drives the reaction to completion. Additionally, a newly developed, grafted surface solid support, is described. This support, the MicroTube, can be used for the synthesis of large numbers of discrete molecules by a patented directed sorting method.

Solid support linker strategies

The selection of an appropriate linker is critical to the success of any strategy for the solid-phase synthesis of small molecule libraries. While the primary function of the linker is to covalently attach the initial substrate to the support, innovative strategies have emerged recently in which linkers fulfill important auxiliary roles. These include the cleavage of compounds into solution leaving no trace of the support attachment site, cleavage via cyclization, cleavage by introduction of additional diversity into the structure, and cleavage whereby portions of the compound are sequentially released into solution.

Solid-phase synthesis of small molecule libraries using double combinatorial chemistry

The first synthesis of a combinatorial library using double combinatorial chemistry is presented. Coupling of unprotected Fmoc-tyrosine to the solid support was followed by Mitsunobu O-alkylation. Introduction of a diacid linker yields a system in which the double combinatorial step can be demonstrated. The resulting library of model compounds was verified by LC-MS analysis.

Combinatorial Chemistry and Molecular Diversity. An Overview

Combinatorial chemistry is no longer viewed as a speculative technique for R&D in the pharmaceutical and agrochemical industries but has become an established important technology. High throughput screening and combinatorial chemistry are altering the character of discovery research. This paper introduces the principles of design and synthesis of small molecule libraries and discusses software being developed in generation of molecular diversity, in molecular design and analysis, in handling the information explosion, in information management, and in decision support to enable drug discovery groups to accelerate the planning and development of libraries, improve work group communication, and facilitate the generation of ideas.